@article{ecc91803e1f34e46b4c9525bff2231f3,
title = "ALS-linked KIF5A ΔExon27 mutant causes neuronal toxicity through gain-of-function",
abstract = "Mutations in the human kinesin family member 5A (KIF5A) gene were recently identified as a genetic cause of amyotrophic lateral sclerosis (ALS). Several KIF5A ALS variants cause exon 27 skipping and are predicted to produce motor proteins with an altered C-terminal tail (referred to as ΔExon27). However, the underlying pathogenic mechanism is still unknown. Here, we confirm the expression of KIF5A mutant proteins in patient iPSC-derived motor neurons. We perform a comprehensive analysis of ΔExon27 at the single-molecule, cellular, and organism levels. Our results show that ΔExon27 is prone to form cytoplasmic aggregates and is neurotoxic. The mutation relieves motor autoinhibition and increases motor self-association, leading to drastically enhanced processivity on microtubules. Finally, ectopic expression of ΔExon27 in Drosophila melanogaster causes wing defects, motor impairment, paralysis, and premature death. Our results suggest gain-of-function as an underlying disease mechanism in KIF5A-associated ALS.",
keywords = "ALS, KIF5A, aggregation, autoinhibition, microtubules",
author = "Pant, {Devesh C.} and Janani Parameswaran and Lu Rao and Isabel Loss and Ganesh Chilukuri and Rosanna Parlato and Liang Shi and Glass, {Jonathan D.} and Bassell, {Gary J.} and Philipp Koch and R{\"u}stem Yilmaz and Weishaupt, {Jochen H.} and Arne Gennerich and Jie Jiang",
note = "Funding Information: We are grateful to the patients and their families for participating in this study. We are grateful for the support and the private fundraising activity “Sternenlicht” of Thorsten Vo{\ss}. The authors would like to thank Drs. David Brenner, Zachary McEachin, members of Jie Jiang, Gary Bassell, Jochen Weishaupt, Philipp Koch, Kenneth Moberg, and Victor Faundez labs for many helpful discussions. We also thank Laura Fox-Goharioon (Emory Integrated Cellular Imaging Core) as well as Gina Tillmann, Lukas Eckrich, and Melita Simic for their technical support. We acknowledge the support of the Core Facility Live Cell Imaging Mannheim (LIMa) at the Medical Faculty Mannheim in using the TCS SP8 confocal microscope (Leica Microsystems). DCP and JP are supported by the Milton Safenowitz Postdoctoral Fellowship from the ALS association (Grants# 22-PDF-605 to DCP and 21-PDF-585 to JP). RY is supported by German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) Walter Benjamin Programme (492655220). LR and AG are supported by National Institutes of Health (NIH) grants R01GM098469 and R01NS114636. LS and GJB are supported by the NIH R01 (R01NS114253 to GJB). The work is partially supported by the NIH R01 grant R01AG068247 to JJ. Funding Information: We are grateful to the patients and their families for participating in this study. We are grateful for the support and the private fundraising activity “Sternenlicht” of Thorsten Vo{\ss}. The authors would like to thank Drs. David Brenner, Zachary McEachin, members of Jie Jiang, Gary Bassell, Jochen Weishaupt, Philipp Koch, Kenneth Moberg, and Victor Faundez labs for many helpful discussions. We also thank Laura Fox‐Goharioon (Emory Integrated Cellular Imaging Core) as well as Gina Tillmann, Lukas Eckrich, and Melita Simic for their technical support. We acknowledge the support of the Core Facility Live Cell Imaging Mannheim (LIMa) at the Medical Faculty Mannheim in using the TCS SP8 confocal microscope (Leica Microsystems). DCP and JP are supported by the Milton Safenowitz Postdoctoral Fellowship from the ALS association (Grants# 22‐PDF‐605 to DCP and 21‐PDF‐585 to JP). RY is supported by German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) Walter Benjamin Programme (492655220). LR and AG are supported by National Institutes of Health (NIH) grants R01GM098469 and R01NS114636. LS and GJB are supported by the NIH R01 (R01NS114253 to GJB). The work is partially supported by the NIH R01 grant R01AG068247 to JJ. Publisher Copyright: {\textcopyright} 2022 The Authors.",
year = "2022",
month = aug,
day = "3",
doi = "10.15252/embr.202154234",
language = "English (US)",
volume = "23",
journal = "EMBO Reports",
issn = "1469-221X",
publisher = "Nature Publishing Group",
number = "8",
}
